Abstract-Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-␣ form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase-mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the ␤-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression. (Circulation. 1998;98:2088-2093.)Key Words: apolipoproteins Ⅲ arteriosclerosis Ⅲ fibrates Ⅲ hypercholesterolemia Ⅲ hyperlipoproteinemia Ⅲ lipids Ⅲ PPAR A vast number of studies confirmed the intimate and causative relationships between dyslipidemias and coronary heart disease. Although hypercholesterolemia is an important underlying cause for coronary heart disease, other dyslipidemias, such as hypoalphalipoproteinemia (low plasma HDL) and hypertriglyceridemia, may be causative in a substantial number of cases. Fibrates are useful for the treatment of hypoalphalipoproteinemia with or without hypertriglyceridemia.1,2 The recommendation for the use of fibrates in certain types of dyslipidemia has gained additional support from a subgroup analysis of the Helsinki Heart Study, 3 which showed that the best preventive efficacy has been achieved in a subset of Ϸ10% of the study population who had a baseline LDL:HDL cholesterol ratio of Ͼ5 and a triglyceride level of 2.3 mmol/L. 4,5 Results from angiographic trials revealed that fibrates retard the progression of coronary atherosclerosis and decrease the number of coronary events. 6,7 Pharmacological Action of FibratesFibrates are generally effective in lowering elevated plasma triglycerides and cholesterol. The magnitude of lipid changes depends, however, on the patient's pretreatment lipoprotein status 8 as well as the relative potency of the fibrate used. 9 The most pronounced effects of fibrates are a decrease in plasma triglyceride-rich lipoproteins (TRLs). Levels of LDL cholesterol (LDL-C) generally decrease in individuals with elevated baseline plasma concentrations, and HDL cholesterol (HDL-C) levels are u...

Comparison of genomic DNA sequences from human and mouse revealed a new apolipoprotein (APO) gene ( APOAV ) located proximal to the well-characterized APOAI/CIII/AIV gene cluster on human 11q23. Mice expressing a human APOAV transgene showed a decrease in plasma triglyceride concentrations to one-third of those in control mice; conversely, knockout mice lacking Apoav had four times as much plasma triglycerides as controls. In humans, single nucleotide polymorphisms (SNPs) across the APOAV locus were found to be significantly associated with plasma triglyceride levels in two independent studies. These findings indicate that APOAV is an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease.

Peroxisome proliferator-activated receptors (PPARs) are key players in lipid and glucose metabolism and are implicated in metabolic disorders predisposing to atherosclerosis, such as dyslipidaemia and diabetes. Whereas PPARgamma promotes lipid storage by regulating adipocyte differentiation, PPARalpha stimulates the beta-oxidative degradation of fatty acids. PPARalpha-deficient mice show a prolonged response to inflammatory stimuli, suggesting that PPARalpha is also a modulator of inflammation. Hypolipidaemic fibrate drugs are PPARalpha ligands that inhibit the progressive formation of atherosclerotic lesions, which involves chronic inflammatory processes, even in the absence of their atherogenic lipoprotein-lowering effect. Here we show that PPARalpha is expressed in human aortic smooth-muscle cells, which participate in plaque formation and post-angioplasty re-stenosis. In these smooth-muscle cells, we find that PPARalpha ligands, and not PPARgamma ligands, inhibit interleukin-1-induced production of interleukin-6 and prostaglandin and expression of cyclooxygenase-2. This inhibition of cyclooxygenase-2 induction occurs transcriptionally as a result of PPARalpha repression of NF-kappaB signalling. In hyperlipidaemic patients, fenofibrate treatment decreases the plasma concentrations of interleukin-6, fibrinogen and C-reactive protein. We conclude that activators of PPARalpha inhibit the inflammatory response of aortic smooth-muscle cells and decrease the concentration of plasma acute-phase proteins, indicating that PPARalpha in the vascular wall may influence the process of atherosclerosis and re-stenosis.

PPAR␥ is a member of the PPAR subfamily of nuclear receptors. In this work, the structure of the human PPAR␥ cDNA and gene was determined, and its promoters and tissue-specific expression were functionally characterized. Similar to the mouse, two PPAR isoforms, PPAR␥1 and PPAR␥2, were detected in man. The relative expression of human PPAR␥ was studied by a newly developed and sensitive reverse transcriptasecompetitive polymerase chain reaction method, which allowed us to distinguish between PPAR␥1 and ␥2 mRNA. In all tissues analyzed, PPAR␥2 was much less abundant than PPAR␥1. Adipose tissue and large intestine have the highest levels of PPAR␥ mRNA; kidney, liver, and small intestine have intermediate levels; whereas PPAR␥ is barely detectable in muscle. This high level expression of PPAR␥ in colon warrants further study in view of the well established role of fatty acid and arachidonic acid derivatives in colonic disease. Similarly as mouse PPAR␥s, the human PPAR␥s are activated by thiazolidinediones and prostaglandin J and bind with high affinity to a PPRE. The human PPAR␥ gene has nine exons and extends over more than 100 kilobases of genomic DNA. Alternate transcription start sites and alternate splicing generate the PPAR␥1 and PPAR␥2 mRNAs, which differ at their 5 -ends. PPAR␥1 is encoded by eight exons, and PPAR␥2 is encoded by seven exons. The 5 -untranslated sequence of PPAR␥1 is comprised of exons A1 and A2, whereas that of PPAR␥2 plus the additional PPAR␥2-specific N-terminal amino acids are encoded by exon B, located between exons A2 and A1. The remaining six exons, termed 1 to 6, are common to the PPAR␥1 and ␥2. Knowledge of the gene structure will allow screening for PPAR␥ mutations in humans with metabolic disorders, whereas knowledge of its expression pattern and factors regulating its expression could be of major importance in understanding its biology.White adipose tissue is composed of adipocytes, which play a central role in lipid homeostasis and the maintenance of energy balance in vertebrates. These cells store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation. Excess of white adipose tissue leads to obesity (1-3), whereas its absence is associated with lipodystrophic syndromes (4). In contrast to the development of brown adipose tissue, which mainly takes place before birth, the development of white adipose tissue is the result of a continuous differentiation/development process throughout life (2, 5). During development, cells that are pluripotent become increasingly restricted to specific differentiation pathways. Adipocyte differentiation results from coordinate changes in the expression of several proteins, which are mostly involved in lipid storage and metabolism, that give rise to the characteristic adipocyte phenotype. The changes in expression of these specialized proteins are mainly the result of alterations in the transcription rates of their genes.Several transcription fac...

Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPAR␣ and PPAR␥ forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPAR␣ is already present in undifferentiated monocytes, PPAR␥ expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPAR␣ resides constitutively in the cytoplasm, whereas PPAR␥ is predominantly nuclear localized. Transient transfection experiments indicate that PPAR␣ and PPAR␥ are transcriptionally active after ligand stimulation. Ligand activation of PPAR␥, but not of PPAR␣, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPAR␣ and PPAR␥ ligands induce apoptosis of macrophages activated with tumor necrosis factor ␣/interferon ␥. Finally, PPAR␥ inhibits the transcriptional activity of the NFB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.

PPARα is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARα also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARα help explain the clinical actions of fibrates, synthetic PPARα agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARα in humans, recent findings have revealed potential adverse effects of PPARα action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARα in metabolic diseases and their associated vascular pathologies. IntroductionNutrient metabolism and energy homeostasis are tightly regulated by endocrine, paracrine, and autocrine signals that control the expression and activity of key metabolic enzymes and transport proteins by transcriptional and posttranscriptional mechanisms. Lipid mediators play a critical role in metabolic control, and the PPARs (NR1Cs), a class of ligand-activated transcription factors, have emerged as master transcriptional regulators of lipid and carbohydrate metabolism. Saturated and unsaturated long-chain fatty acids (FAs) and their eicosanoid derivatives are natural activators of this subclass of nuclear receptors. Increased recognition of a role for PPARs in metabolic regulation came following the discovery that the hypolipidemic fibrates and the insulin sensitizers thiazolidinediones were synthetic ligands for PPARα (NR1C1; refs. 1, 2) and PPARγ (NR1C3; ref. 3), respectively. PPARδ (NR1C3), also known as PPARβ, is the third PPAR isotype.Accumulating evidence supports a link between the 3 PPARs and diabetes, obesity, dyslipidemia, and inflammation. PPARα controls liver and skeletal muscle lipid metabolism, and glucose homeostasis. PPARα influences intracellular lipid and carbohydrate metabolism through direct transcriptional control of genes involved in peroxisomal and mitochondrial β-oxidation pathways, FA uptake, and triglyceride (TG) catabolism. Moreover, preclinical data suggest a role for PPARα in body weight control, supporting the use of PPARα agonists to treat obesity (4). Mice deficient in PPARα exhibit a delayed response to inflammatory stimuli (5). Several clinical trials demonstrate the efficiency of fibrates at decreasing circulatory inflammatory markers and reducing the progression of coronary atherosclerotic lesions. The ability of PPARα to improve

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.

The development of colorectal cancer, one of the most frequent cancers, is influenced by prostaglandins and fatty acids. Decreased prostaglandin production, seen in mice with mutations in the cyclooxygenase 2 gene or in animals and humans treated with cyclooxygenase inhibitors, prevents or attenuates colon cancer development. There is also a strong correlation between the intake of fatty acids from animal origin and colon cancer. Therefore, the peroxisome proliferator-activated receptor gamma (PPARgamma), a downstream transcriptional mediator for prostaglandins and fatty acids which is highly expressed in the colon may be involved in this process. Activation of PPARgamma by two different synthetic agonists increased the frequency and size of colon tumors in C57BL/6J-APCMin/+ mice, an animal model susceptible to intestinal neoplasia. Tumor frequency was only increased in the colon, and did not change in the small intestine, coinciding with the colon-restricted expression of PPARgamma. Treatment with PPARgamma agonists increased beta-catenin levels both in the colon of C57BL/61-APCMin/+ mice and in HT-29 colon carcinoma cells. Genetic abnormalities in the Wnt/wingless/APC pathway, which enhance the transcriptional activity of the beta-catenin-T-cell factor/lymphoid enhancer factor 1 transcription complex, often underly the development of colon tumors. Our data indicate that PPARgamma activation modifies the development of colon tumors in C57BL/61-APCMin/+ mice.